In the field of magnetic resonance imaging, various lanthanide chelates of cyclen-derivative macrocyclic chelating agents have been proposed. Two, GdHP-DO3A (ProHance from Squibb) and GdDOTA (Dotarem from Guerbet), are available commercially. These macrocyclic chelating agents form particularly stable chelate complexes with the contrast-generating paramagnetic metal ions and thus are suitable carriers for the metal ions to ensure appropriate biodistribution and elimination.
Cyclen itself (1,4,7,10-tetraazacyclododecane) is a key and somewhat expensive intermediate in the preparation of these macrocyclic chelants.
Production of cyclen's tetraaza macrocycle can be by a variety of synthetic routes, for example via diamine:diamine or triamine:monoamine cyclic condensations such as are described by Tweedle in EP-A-232751 and EP-A-292689. Such condensations generally produce N-substituted cyclen derivatives in which the ring nitrogens are protected by tosyl or mesyl groups which then have to be removed before the cyclen can be alkylated to yield the macrocyclic chelating agent. Detosylation involves high temperature treatment with sulphuric acid, a commercially unattractive route. Detosylation moreover requires continuous extraction with chloroform over a period of days making it an environmentally unattractive procedure. Mesylation and demesylation are similarly difficult and unattractive on a commercial scale.
We have now found that macrocyclic tetraazacycloalkanes, such as cyclen, can advantageously be prepared from acyclic tetraazaalkanes by a cyclization process which involves first coupling the four nitrogens of the starting material to a bridging agent to produce a tricyclic intermediate and then converting this intermediate to the tetraaza-macrocycle.
In effect, the bridging moiety in the tricyclic intermediate, which can be a monoatomic or polyatomic entity, serves as a template to present the terminal nitrogens of the initially acyclic tetramine in a suitable configuration for the ring closing cyclization. Indeed, in one embodiment, the bridging moiety can itself provide the molecular subunit which forms the bridge between the terminal nitrogens to form the tetraaza-macrocycle.